James Parkinson's Chimera: syndrome or disease?

It is 200 years since James Parkinson published An Essay on the Shaking Palsy. While his monograph continues to be acclaimed for its precedence and clarity of description, what is often overlooked is the originality of Parkinson's ideas. Here we show that he appreciated the weakness of the systematic 18th century nosologies, which presupposed that medical species, the building blocks of these Linnaean taxonomic schemes, were as distinct as plant and animal species; and that Parkinson made a conceptual leap about combinations of clinical phenomena in recurring patterns, now recognised to be one of the germs of neurological thinking about syndromes. The Essay's written style underpins another aspect of significance to contemporary neurological practice - an inherent intellectual humility. In this commemorative year we locate the continuing importance of the related notions of syndrome and disease in successive frameworks of knowledge about the shaking palsy. Syndrome and disease are interpreted as dual character concepts, one clinically-based and the other restricted to pathophysiological causation. They both remain fundamental to understanding Parkinson's syndrome-disease today.

E. Graeme Robertson--dynamics in fluid and light.

An eponymous lecture at the Australian and New Zealand Association of Neurologists Annual Scientific Meeting commemorates E. Graeme Robertson (1903-75), and some neurologists will know that particular Australian practices in clinical neurology, so far as they exist, have origins in his career. This is a historical article on the literary record of a man who had his own sense of history--an affinity with the past as well as an awareness of future generations of readers. He wrote authoritative texts on pneumoencephalography before new technology made it obsolete, and he produced a series of books on decorative architectural cast iron in Australian cities. A talent for visual interpretation seems to have drawn him to both of these topics; a common theme is contrast between light and dark, which is expatiated in images and in clear, well-written prose in his publications. We review his medical writings, including some largely forgotten principles of cerebrospinal fluid physics that he discovered when researching pneumoencephalography. We also explore his obsession with cast iron--its architectural historical significance, his techniques for photographing it, and some of the ways that it related to his life's work as a clinical neurologist.

A clinico-pathological study of subtypes in Parkinson's disease.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25%), tremor dominant (31%), non-tremor dominant (36%) and rapid disease progression without dementia (8%) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70% of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

Prognostic predictors have not been defined for progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). Subtypes of both disorders have been proposed on the basis of early clinical features. We performed a retrospective chart review to investigate the natural history of pathologically confirmed cases of PSP and MSA. Survival data and several clinically relevant milestones, namely: frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters and placement in residential care were determined. On the basis of early symptoms, we subdivided cases with PSP into 'Richardson's syndrome' (RS) and 'PSP-parkinsonism' (PSP-P). Cases of MSA were subdivided according to the presence or absence of early autonomic failure. Sixty-nine (62.7%) of the 110 PSP cases were classified as RS and 29 (26.4%) as PSP-P. Of the 83 cases of MSA, 42 (53.2%) had autonomic failure within 2 years of disease onset. Patients with PSP had an older age of onset (P < 0.001), but similar disease duration to those with MSA. Patients with PSP reached their first clinical milestone earlier than patients with MSA (P < 0.001). Regular falls (P < 0.001), unintelligible speech (P = 0.04) and cognitive impairment (P = 0.03) also occurred earlier in PSP than in MSA. In PSP an RS phenotype, male gender, older age of onset and a short interval from disease onset to reaching the first clinical milestone were all independent predictors of shorter disease duration to death. Patients with RS also reached clinical milestones after a shorter interval from disease onset, compared to patients with PSP-P. In MSA early autonomic failure, female gender, older age of onset, a short interval from disease onset to reaching the first clinical milestone and not being admitted to residential care were independent factors predicting shorter disease duration until death. The time to the first clinical milestone is a useful prognostic predictor for survival. We confirm that RS had a less favourable course than PSP-P, and that early autonomic failure in MSA is associated with shorter survival.

The Lhermitte phenomenon: variant forms and their significance.

Typical Lhermitte phenomenon (tingling sensations moving down the limbs or trunk on neck flexion) is a sign of intrinsic spinal cord pathology, most commonly cervical spinal cord demyelination. The phenomenon has several variant forms, and each has a different pathological significance. A delayed typical Lhermitte phenomenon can follow contusion of the spinal cord from neck trauma. Reverse Lhermitte phenomenon induced by neck extension is usually produced by extrinsic compression of the cervical spinal cord. Upward moving paraesthesia with neck flexion (inverse Lhermitte phenomenon) is relatively rare, and can be a sign of myelopathy from nitrous oxide inhalation.

John Ruskin's relapsing encephalopathy.

John Ruskin (1819-1900) is chiefly remembered for his works on painting and architecture, and for his powerful and original prose style. In middle age, he suffered recurring episodes of delirium with visual hallucinations and delusions. At about the same time, his writing developed a disjointed polemical character, with cryptic and intemperate elements that disorientated some readers. The nature of Ruskin's 'madness' is a key to understanding his later writing career but the psychiatric explanations given by many of his literary biographers seem unsatisfactory. Ruskin left numerous clues about the illness in his diaries, correspondence and publications. It is likely that he had a relapsing-progressive neurological disorder with neuropsychiatric manifestations. It could have been a fluctuating metabolic or immunological encephalopathy, but the diagnosis that best fits the time course of his illness and the prior history of mood disorder and of migraine with aura is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Whatever the pathology, its first effects on frontal lobe function may have actually enhanced Ruskin's creative energy for a long time before stepwise cognitive impairment degraded his ability to write.

Patterns of levodopa response in Parkinson's disease: a clinico-pathological study.

Patients with Parkinson's disease who develop disabling levodopa-induced motor fluctuations have a stronger therapeutic response than those who experience a more modest but stable response. A difference in the histopathological lesion between the two groups might be responsible. Case records from 97 patients with pathologically proven Parkinson's disease were reviewed to determine the pattern of levodopa response. Pathological findings for fluctuating and non-fluctuating cases were compared. Patients with motor fluctuations had a younger age of onset and longer disease course (P < 0.001), although mean age at death was almost the same. Four milestones of advanced disease (frequent falls, visual hallucinations, cognitive disability and need for residential care) occurred at a similar time from death in each group; this interval was not proportionate to the disease duration. There were no significant differences in the severity or distribution of Lewy body or other pathologies. Irrespective of the pattern of levodopa response, patients reach a common pathological endpoint at a similar age, and the duration and manifestations of end-stage disease are alike. A non-linear or exponential time relationship may govern the late clinical and pathological progression of Parkinson's disease.

Sporadic encephalitis lethargica.

Three women (aged 21-36 years) developed acute illnesses that were similar to epidemic encephalitis lethargica. Each presented with a neuropsychiatric disturbance that was succeeded by pyrexia, a fluctuating conscious state and involuntary movements including oculogyria. Cerebrospinal fluid examination showed a predominantly lymphocytic pleocytosis (64-120x10(6) cells/L) and oligoclonal bands were detected in two cases. Two patients died, while the third made a gradual recovery. Post-mortem examination in the two fatal cases showed changes of lymphocytic meningitis and focal diencephalic lymphocytic infiltration, although these changes were mild relative to the effects of the clinical illness. The diagnosis of sporadic encephalitis lethargica relies on identifying shared clinical features with the past epidemic disease plus circumstantial evidence of immunological activity from laboratory investigations and some tests of exclusion of other disorders.

Staying on the surface.

Every neurologist needs to develop an effective technique to diagnose and manage non-organic disorders, although there are different ways to go about it. The complex relationship that exists between functional and organic illness is an inescapable theme in daily neurological practice. Usually, it is better to read these case stories by examining their surface detail rather than to try to understand their psychological depth.

Looking for clues.

At certain moments in clinical practice, one can seem to possess the powers of a Sherlock Holmes to search out clues and deduce the diagnosis. Many neurologists are aware of links between the workings of detective fiction and the methods of problem-solving in neurological cases. One similarity concerns the professional counterpart of the conventional detective story, the single case report.

Reading a story.

Case delineation in clinical medicine is the technique of creating a narrative that allows the appropriate scientific knowledge to be brought to bear. Neurologists get to be good at this type of story reading and telling from dealing with clinical stories which are relatively long and complicated. These skills are evident whenever working neurologists gather to discuss case material, or when studying their written clinical communications. The purpose of the article is to analyze this aspect of everyday neurological practice by looking at some of the general principles of story telling and appreciation.

Evolution of motor fluctuations in Parkinson's disease: a longitudinal study over 6 years.

A prospective longitudinal 6-year study of 34 patients with Parkinson's disease from the time of initiation of drug treatment explored changes in the motor response to L-dopa over the early to mid disease course. Motor fluctuations developed in 41% after a mean L-dopa treatment interval of 25 months and dyskinesia developed in 53% after a mean of 15 months' treatment. Patients who developed fluctuations had a significantly better response to L-dopa than nonfluctuators. Nonfluctuators also had significantly greater "midline" motor disability affecting cranial and truncal muscles and gait. The development of motor fluctuations may simply reflect a retained capacity to respond to L-dopa as endogenous dopaminergic neurotransmission declines with progressive nigral cell loss. Many patients who show no sign of motor fluctuation 5 or 6 years into the disease course have a relatively blunted response to L-dopa. The proportion of such cases seems to correspond to the percentage that have coexisting striatal pathologic changes in postmortem studies.

Motor response to levodopa in patients with parkinsonian motor fluctuations: a follow-up study over three years.

To clarify the way in which the clinical response to levodopa changes with the progression of Parkinson's disease, a longitudinal study was performed to quantify motor response characteristics to single doses of levodopa by mouth over three years in 23 patients with fluctuating motor function. A significant increase in motor disability in "on" (time of peak motor improvement) and "off" (before levodopa dose) phases occurred and "on" phase dyskinesia increased by 24%, though the amplitude of motor response was conserved. There was no evidence of progressive loss of response of certain motor deficits affecting axial muscles and gait. The mean duration of motor response decreased by 17%. Both shortening of response duration and increase in "off" phase disability contribute to the development of motor fluctuations. A short response time to the levodopa test dose was not an invariable finding in patients with severe fluctuations, whereas all had large response amplitudes and high "off" phase disability scores. Patients who have developed motor fluctuations may continue to respond to dopaminergic treatment until late in the disease course, despite the unstable nature of their responses.

Dietary factors in the management of Parkinson's disease.

Oral administration of L-dopa is currently the most effective way to treat the cerebral dopamine deficiency which causes Parkinson's disease. Unfortunately, many patients with advanced Parkinson's disease develop an unstable pattern of response to L-dopa because of fluctuating delivery of the drug to the brain. Diet contributes to this problem through its adverse effects on L-dopa pharmacokinetics. This article reviews dietary strategies to improve responsiveness to pharmaceutical L-dopa treatment and the potential use of food as a source of L-dopa. Nutritional factors concerning weight loss and energy balance in Parkinson's disease are also discussed. A set of dietary guidelines is developed to assist clinical nutritionists and neurologists in the practical management of patients with Parkinson's disease.

Response to L-dopa and evolution of motor fluctuations in the early phase of treatment of Parkinson's disease.

Twenty patients with Parkinson's disease were studied during the early phase of L-dopa treatment to clarify the development and progression of Parkinsonian motor fluctuations. Two patients had developed symptomatic motor fluctuations of moderate severity and another 3 had mild fluctuations. Both the initial response to L-dopa and the amplitude of response to a L-dopa test dose after a mean follow up period of 30 months were significantly greater for the fluctuating patients compared with those without fluctuation (p < 0.05). Although severe motor fluctuations do not usually develop until a number of years of L-dopa treatment have elapsed, this study shows that motor fluctuations can be detected quite early in the disease course and tend to appear in those patients who respond best to L-dopa.

Motor effects of broad beans (Vicia faba) in Parkinson's disease: single dose studies.

Broad beans (Vicia faba) are a natural source of L-dopa. To investigate a possible role for this substance in the treatment of Parkinsonian motor oscillations, we carried out single dose studies of Vicia faba pod mixture plus carbidopa in six patients. Motor responses of equivalent magnitude to those of conventional L-dopa medication occurred in five cases with mean onset of 39 min and mean duration of 104 min. Vicia faba meals produced comparable L-dopa blood levels to fasting standard tablet doses and recovery studies yielded 0.25% L-dopa per weight of bean pod mixture. Vicia faba contains sufficient L-dopa to be pharmacologically active in patients with Parkinson's disease and can potentially be incorporated into dietary strategies to manage Parkinsonian motor oscillations.

Intermittent subcutaneous apomorphine injection treatment for parkinsonian motor oscillations.

Eight patients with severe Parkinsonian motor oscillations have been treated with the dopamine receptor agonist apomorphine by intermittent subcutaneous self-injection as an adjunct to oral anti-Parkinsonian medication. The dopamine receptor antagonist domperidone was also given by mouth to prevent nausea. Six patients remain on chronic treatment (mean period 6.5 months) with improved control of motor function in each case. Four have had major enhancement of their quality of life. Benefits of this treatment stem from the training of patients to use intelligent behaviour to administer a promptly acting and effective pharmacological agent, thereby exercising a degree of direct control over previously unpredictable variations in motor performance.

Comparison of motor response to apomorphine and levodopa in Parkinson's disease.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.